KR100645372B1 - Bicyclic tetrahydrofuran lactone derivatives, and process for preparing them - Google Patents

Abstract

Novel bicyclic tetrahydrofuran lactone derivatives, and a preparation process thereof are provided to serve useful intermediates for synthesis of natural products, and prepare the compounds simply. The bicyclic tetrahydrofuran lactone derivatives represented by the formula(1) are provided, wherein n is 1 or 2; R is phenyl group optionally substituted by C1-C6 alkyl group, C1-C6 alkoxy group, hydroxy group or C1-C6 hydroxyalkyl group. The bicyclic tetrahydrofuran lactone derivatives represented by the formula(1) are prepared by intramolecular cyclizing tetrahydrofuran-allenic acid derivatives represented by the formula(2) in the presence of phenyl halide, palladium catalyst and base, wherein the reaction solvent is diethylether, tetrahydrofuran, dichloromethane, dimethylformamide, ethylacetate or chloroform; the palladium catalyst is tetrakis(triphenylphosphin) palladium; the base is carbonate, hydrogen carbonate or sulfate of alkali metals or alkali earth metals; and the reaction temperature is 0 to 90 deg.C.

Description

Bicyclic tetrahydrofuran lactone compounds and process for preparing the same

The present invention relates to a bicyclic tetrahydrofuran lactone compound and a preparation method thereof, and more particularly, to perform an intramolecular cyclization reaction of a tetrahydrofuran-alylene acid derivative under the presence of a phenyl halide, a palladium catalyst and a base. The present invention relates to a bicyclic tetrahydrofuran lactone compound prepared by the following Chemical Formula 1 and a method for preparing the same.

[Formula 1]

In Formula 1, n is 1 or 2; R represents a phenyl group or a substituted phenyl group, wherein the substituent is selected from C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, hydroxy groups, and C ₁ -C ₆ hydroxyalkyl groups.

Tetrahydrofuran (Tetrahydrofuran) derivatives are known to be included in many substances in nature, etc., and has been studied as a core structure of natural or synthetic pharmaceuticals having in vivo activity. In particular, the stereoselective tetrahydrofuran derivative having a cis relationship at the C-2 and 5 positions is known to exhibit good activity in vivo. For example, bicyclic tetrahydrofuran or bicyclic perhydrofuropyran compounds can be found in many natural products ( J. Am. Chem. Soc. , 1998, 120 , 9967-9968; Org. Lett. , 2001, 3 , 979-982; Angew. Chem., Int. Ed. 2001, 40 , 1262-1265).

(+) - elsso lactone (Altholactone) are polyalkenyl thiazole (Polyalthia) or Goniometer Tallahassee mousse - in the material extracted from a type of time period Proteus (Goniothalamus-giganteus), showing the activation effect on P 388 leukemia (in vivo) It is known to have some cytotoxicity ( in vitro ). (+)-Elsolactone is structurally based on tetrahydrofuran and lactone ( Tetrahedron , 1994, 50 , 11315-11320).

In addition, Plakortones AD constitutes a new class of cardiac disease SR-Ca ²⁺ -pumping ATPase activators and is involved in correcting irregularities in heart disease relaxation. Among these derivatives, Prakortones D is known to have the best activity. In addition, Plakortones BF is known to have cytotoxicity ( in vitro ) to fibrosarcoma cells infected from mice. The above-mentioned Plakortones derivatives structurally have tetrahydrofuran and lactone as basic structures ( J. Am. Chem. Soc . 2002, 124 , 9718-9719).

As described above, compounds containing tetrahydrofuran and lactone as basic structures have a high value as a core material in medicine and fine chemical fields, and thus, in the art, synthesis of a tetrahydrofuran lactone compound having a new structure is There is an urgent need.

It is an object of the present invention to provide a bicyclic tetrahydrofuran lactone compound having a novel structure.

The present invention also provides a method for efficiently synthesizing two cyclic tetrahydrofuran lactone compounds by performing an intramolecular cyclization reaction of a tetrahydrofuran-alene acid derivative under the presence of a phenyl halide, a palladium catalyst and a base. Has a different purpose.

The present invention is characterized by a tetrahydrofuran lactone compound having a novel structure represented by the following formula (1).

[Formula 1]

In Formula 1, n is 1 or 2; R represents a phenyl group or a substituted phenyl group, wherein the substituent is selected from C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, hydroxy groups, and C ₁ -C ₆ hydroxyalkyl groups.

In addition, the present invention is carried out an intramolecular cyclization reaction of the tetrahydrofuran- allene acid derivative represented by the following formula (2) in the presence of a phenyl halide, a palladium catalyst and a base two cyclic tetrahydro represented by the following formula (1) Another method is to prepare a furan lactone compound.

In Scheme 1, n is 1 or 2; R represents a phenyl group or a substituted phenyl group, wherein the substituent is selected from C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, hydroxy groups, and C ₁ -C ₆ hydroxyalkyl groups.

Referring to the present invention in more detail as follows.

The bicyclic tetrahydrofuran lactone compound represented by the formula (1) synthesized by the present invention is a novel compound, and is a novel structural material that can be usefully used in medicine and fine chemistry as an active substance of medicine.

In the bicyclic tetrahydrofuran lactone compound represented by Chemical Formula 1, preferably, the following compounds may be included:

n is 1; R represents a phenyl group or substituted phenyl group, wherein the substituent is selected from the compounds selected from an alkoxy group of C ₁ -C ₆ alkyl group and C ₁ -C _6, or an

n is 2; R is a compound of a phenyl group, or a substituted phenyl group, wherein the substituents are selected from alkoxy groups of the alkyl group of C ₁ -C ₆ and C ₁ -C _6.

In addition, the present invention includes a method for preparing a tetrahydrofuran lactone compound represented by the formula (1), while performing an intramolecular cyclization reaction of a tetrahydrofuran compound containing allene acid, the intramolecular cyclization reaction Is carried out under the conditions in which the phenyl halide, the palladium catalyst and the base are present to efficiently prepare the compound represented by the formula (1).

As the phenyl halide compound, particularly preferably, phenyl iodide (PhI) is used in carrying out the preparation method according to the present invention. The phenyl halide may be used in the range of 1.0 to 6.0 equivalents based on the tetrahydrofuran-alylene acid derivative represented by Formula 2 used as a starting material.

The catalyst may include tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ) or palladium chloride (PdCl ₂ ) as a palladium compound. The palladium catalyst may be used in the range of 0.01 to 1.0 equivalents based on the tetrahydrofuran-alylene acid derivative represented by Formula 2 used as a starting material.

The base may be selected from carbonates, hydrogencarbonates, and sulfates of alkali or alkaline earth metals, and particularly preferably potassium potassium carbonate (K ₂ CO ₃ ). The base is used in the range of 1.0 to 6.0 equivalents based on the tetrahydrofuran-alylene acid derivative represented by Formula 2 used as a starting material.

As the reaction solvent, a conventional organic solvent may be used. Specifically, a single solvent or a mixed solvent selected from diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, ethyl acetate, and chloroform may be used. Next, dimethylformamide is used.

The reaction temperature is to be maintained in the range of 0 ℃ to 90 ℃, the reaction time is approximately 3 to 5 hours is sufficient.

The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited by the following examples.

Example 1. 5-phenyl-6a- (1-phenyl-vinyl) -tetrahydro-puro [3,2-b] furan-2-one

(5-phenyl-3-vinylidene-tetrahydro-furan-2-yl) -acetic acid (32 mg, 0.12 mmol) with Pd (PPh ₃ ) ₄ (14 mg, 0.012 mmol), K ₂ CO ₃ (84 mg, 0.61 mmol) was dissolved in 3 mL of dimethylformamide, PhI (68 μL, 0.61 mmol) was added, and then 85 Stir at 4 ° C. for 4 h. After the reaction was completed, H ₂ O was added and stirred for about 5 minutes. The reaction mixture was diluted with ethyl acetate, washed with H ₂ O and NaCl, and the organic solvent layer was separated from the mixture and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the remaining material was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:15, v / v) to give the product (26 mg, 62%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.47-7.28 (m, 10H), 5.57 (d, 1H, J = 5.4 Hz), 5.37 (d, 1H, J = 5.4 Hz), 4.97-4.90 (m, 1H), 4.80 (t, 1H, J = 4.8 Hz), 2.96-2.68 (m, 3H), 2.58-2.49 (m, 1H).

Example  2. 5-para- Tolyl -6a- (1- Phenyl -vinyl)- Tetrahydro - Furo [3,2-b] furan 2-on

(5-Para-tolyl-3-vinylidene-tetrahydro-furan-2-yl) -acetic acid (35 mg, 0.14 mmol) with Pd (PPh ₃ ) ₄ (14 mg, 0.012 mmol), K ₂ CO ₃ (84 mg, 0.61 mmol) was dissolved in 3 mL of dimethylformamide, PhI (68 μL, 0.61 mmol) was added, and then 85 Stir at 4 ° C. for 4 h. After the reaction was completed, H ₂ O was added and stirred for about 5 minutes. The reaction mixture was diluted with ethyl acetate, washed with H ₂ O and NaCl, and the organic solvent layer was separated from the mixture and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the remaining material was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:15, v / v) to give the product (27 mg, 58%).

¹ H NMR (300MHz, CDCl ₃ ): δ 7.71-7.62 (m, 2H), 7.38-7.17 (m, 8H), 5.70 (d, 1H), 5.30 (d, 1H), 4.94 (t, 1H), 4.38-4.34 (m, 1H), 2.70-2.52 (m, 3H), 2.37-2.25 (m, 3H).

Example 3. 5- (4-methoxyphenyl) -6a- (1-phenyl-vinyl) -tetrahydro-puro [3,2-b] furan-2-one

(5- (4-methoxyphenyl) -3-vinylidene-tetrahydro-furan-2-yl) -acetic acid (34 mg, 0.12 mmol) and Pd (PPh ₃ ) ₄ (14 mg, 0.012 mmol), K ₂ CO ₃ (84 mg, 0.61 mmol) was dissolved in 3 mL of dimethylformamide, PhI (68 μl, 0.61 mmol) was added, and then 85 Stir at 4 ° C. for 4 h. After the reaction was completed, H ₂ O was added and stirred for about 5 minutes. The reaction mixture was diluted with ethyl acetate, washed with H ₂ O and NaCl, and the organic solvent layer was separated from the mixture and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the remaining material was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:15, v / v) to give the product (27 mg, 61%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.71-7.64 (m, 2H), 7.36-6.82 (m, 7H), 5.70 (d, 1H), 5.30 (d, 1H), 4.89 (t, 1H), 4.37-4.35 (m, 1H), 3.79 (s, 3H), 2.72-2.51 (m, 3H), 2.35-2.22 (m, 1H).

Example 4. 2-phenyl-3a- (1-phenyl-vinyl) -hexahydro-furo [3,2-b] pyran-5-one

(5-phenyl-3-vinylidene-tetrahydro-furan-2-yl) -propionic acid (60 mg, 0.25 mmol) with Pd (PPh ₃ ) ₄ (29 mg, 0.025 mmol), K ₂ CO ₃ (170 mg, 1.23 mmol) was dissolved in 6 mL of dimethylformamide, PhI (138 μl, 1.23 mmol) was added, and then 85 Stir at 4 ° C. for 4 h. After the reaction was completed, H ₂ O was added and stirred for about 5 minutes. The reaction mixture was diluted with ethyl acetate, washed with H ₂ O and NaCl, and the organic solvent layer was separated from the mixture and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the remaining material was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:15, v / v) to give the product (52 mg, 67%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 7.45-7.28 (m, 10 H), 5.63 (s, 1 H), 5.33 (s, 1 H), 4.90 (t, 1 H, J = 7.5 Hz), 4.33 (t, 1H, J = 3.3 Hz), 3.04 (m, 1H, J = 6.0 Hz), 2.85-2.73 (m, 1H), 2.59-2.43 (m, 2H), 2.31-2.21 (m, 1H), 2.17-2.09 (m, 1 H).

Example 5. 2-Para-tolyl-3a- (1-phenyl-vinyl) -hexahydro-furo [3,2-b] pyran-5-one

(5-Para-tolyl-3-vinylidene-tetrahydro-furan-2-yl) -propionic acid (61 mg, 0.25 mmol) with Pd (PPh ₃ ) ₄ (29 mg, 0.025 mmol), K ₂ CO ₃ (170 mg, 1.23 mmol) was dissolved in 6 mL of dimethylformamide, PhI (138 μl, 1.23 mmol) was added, and then 85 Stir at 4 ° C. for 4 h. After the reaction was completed, H ₂ O was added and stirred for about 5 minutes. The reaction mixture was diluted with ethyl acetate, washed with H ₂ O and NaCl, and the organic solvent layer was separated from the mixture and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the remaining material was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:15, v / v) to give the product (50 mg, 63%).

¹ H NMR (300MHz, CDCl ₃ ): δ 7.65 (d, 2H), 7.45-7.17 (m, 7H), 5.64 (s, 1H), 5.29 (s, 1H), 5.06 (t, 1H), 4.21- 4.18 (m, 1H), 2.70-2.53 (m, 3H), 2.34 (s, 3H), 2.29-2.22 (m, 2H), 1.95-1.82 (m, 1H).

Example 6. 2- (4-methoxyphenyl) -3a- (1-phenyl-vinyl) -hexahydro-furo [3,2-b] pyran-5-one

(5- (4-methoxyphenyl) -3-vinylidene-tetrahydro-furan-2-yl) -propionic acid (61 mg, 0.25 mmol) and Pd (PPh ₃ ) ₄ (29 mg, 0.025 mmol), K ₂ CO ₃ (170 mg, 1.23 mmol) in 6 mL of dimethylformamide, PhI (138 μl, 1.23 mmol) After adding 85 Stir at 4 ° C. for 4 h. After the reaction was completed, H ₂ O was added and stirred for about 5 minutes. The reaction mixture was diluted with ethyl acetate, washed with H ₂ O and NaCl, and the organic solvent layer was separated from the mixture and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the remaining material was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:15, v / v) to give the product (57 mg, 73%).

¹ H NMR (300MHz, CDCl ₃ ): δ 7.65 (d, 2H), 7.45-7.17 (m, 5H), 6.80 (d, 2H), 5.64 (s, 1H), 5.29 (s, 1H), 5.01 ( t, 1H), 4.22-4.19 (m, 1H), 3.79 (s, 3H), 2.76-2.53 (m, 3H), 2.34 (s, 3H), 2.25-2.21 (m, 2H), 1.93-1.81 ( m, 1 H).

As described above, the present invention is a stereoselective two-cyclic tetrahydrofuran lactone compound having a cis relationship at the C-2,5 position and the aforementioned novel compound with phenyl halide, palladium catalyst and base. It is possible to provide a method for synthesizing effectively by a very simple method of inducing intramolecular cyclization reaction of tetrahydrofuran-alenic acid derivatives under the following conditions. In particular, the bicyclic tetrahydrofuran lactone compound according to the present invention can be usefully used as an important intermediate for natural product synthesis.

Claims (10)

Two cyclic tetrahydrofuran lactone compounds represented by the following formula (1): [Formula 1]

In Formula 1, n is 1 or 2; R represents a phenyl group or a substituted phenyl group, wherein the substituent is selected from C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, hydroxy groups, and C ₁ -C ₆ hydroxyalkyl groups. The compound of claim 1, wherein n is 1; R is a phenyl group or a substituted phenyl group, said substituent being selected from C ₁ -C ₆ alkyl groups and C ₁ -C ₆ alkoxy groups. The compound of claim 1, wherein n is 2; R is a phenyl, or substituted phenyl group, wherein the substituents are C ₁ -C ₆ and wherein the selected from the group consisting of alkyl groups and C ₁ -C ₆ alkoxy group is a compound. Under the conditions in which the phenyl halide, the palladium catalyst and the base are present, the two cyclic groups represented by the following Chemical Formula 1 are characterized by performing an intramolecular cyclization reaction of the tetrahydrofuran-alylene acid derivative represented by the following Chemical Formula 2. Method for preparing tetrahydrofuran lactone compound:

[Formula 1]

In Formula 1 or 2, n is 1 or 2; R represents a phenyl group or a substituted phenyl group, wherein the substituent is selected from C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkoxy groups, hydroxy groups, and C ₁ -C ₆ hydroxyalkyl groups. The method of claim 4, wherein the reaction solvent is selected from diethyl ether, tetrahydrofuran, dichloromethane, dimethylformamide, ethyl acetate, and chloroform. 5. The method according to claim 4, wherein the phenyl halide is used in an amount of 1.0 to 6.0 equivalents. The method according to claim 4, wherein the palladium catalyst is 0.01 to 1.0 equivalent of tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ). The method of claim 4, wherein the base is selected from carbonates, hydrogencarbonates, and sulfates of alkali or alkaline earth metals. 9. The method of claim 8, wherein the base is used in an amount of 1.0 to 6.0 equivalents of potassium carbonate (K ₂ CO ₃ ). The method of claim 4, wherein the reaction temperature is in the range of 0 ° C to 90 ° C.